Bonnie F. Sloane, Ph.D.
Dr. Sloane’s laboratory has a longstanding interest in the roles of proteases in development and progression of cancer. Their primary emphasis is proteolytic pathways in tumors and their cellular microenvironment in the progression of premalignant breast disease to invasive carcinomas. Her research group has established a role for lysosomal proteases, primarily the cysteine protease cathepsin B, and the endogenous inhibitors of cysteine cathepsins (the cystatins and stefins) in malignant progression. They were the first group to uncover molecular mechanisms for the increased expression of cathepsin B in human tumors and to identify binding partners responsible for alterations in localization of cathepsin B in tumors. This includes the association of cathepsin B with caveolae on the cell surface via the direct binding of procathepsin B to S100A10, p11 or the light chain of the annexin II heterotetramer, in complex with the heavy chain annexin II. They have confirmed this association in a number of types of tumors, including inflammatory breast cancer (IBC). IBC is a highly malignant cancer that disproportionately affects young women, occurring more frequently in women of North African and African-American origin and thus important to our local Detroit community. Further studies on IBC, proteases and lymphangiogenesis are ongoing in our laboratory and with Dr. Cavallo-Medved at the University of Windsor and Dr. Mostafa Mohamed at Cairo University.
The Sloane group has been a leader in applying live-cell imaging to the protease field, in our case to the study of proteases in breast cancer. Our impetus for so doing is the need to study protease activity and proteolytic cascades if we are to exploit the potential of proteases as biomarkers, therapeutic targets or surrogate endpoints. Our laboratory is currently working toward all of those goals. For this purpose, we have established new assays to follow proteolysis by live human breast cells in real time as they form 3-dimensional structures in matrices and migrate through the matrices, thus analyzing proteolysis in four dimensions. We have employed these assays to follow the interactions among breast tumor cells and tumor-associated cells in an effort to determine: 1) whether the various cellular components comprising a tumor use proteolysis to perform their functions (e.g., is there proteolysis associated with infiltration of fibroblasts and macrophages into tumors? With endothelial cell migration and formation of neovessels?); 2) what are the contributions of the various cellular components to collective tumor proteolysis; and 3) what is the contribution of cell:cell interactions to collective tumor proteolysis. We have expanded our analyses to determine how kinase pathways and cytokine/chemokine pathways intersect with and regulate proteolytic pathways and the role(s) of tumor-associated cells in these processes. Our current work focuses on premalignant breast disease. Via our live-cell imaging assays and novel organotypic model systems, we are defining pathways that increase or decrease the transition from a non-invasive through a pre-invasive to an invasive phenotype. We are working to translate the imaging techniques to make treatment decisions about patients with ductal carcinomas in situ, the 4th most prevalent cancer in women in this country.
Ongoing collaborative studies, with Dr. Mattingly and Drs. Haywood and Matrisian of Vanderbilt University, are directed toward defining proteolytic pathways and their intersections with kinase and chemokine/cytokine pathways in tumors and the tumor microenvironment. The goal of these studies is to identify mechanisms by which the tumor microenvironment alters proteolysis in order to design therapeutic strategies to target interactions between the tumor and its microenvironment.
- Graduate Students
- Jennifer Rothberg (Ph.D. candidate in Cancer Biology; NIH Minority Predoctoral Trainee)
- Bernadette Victor (Ph.D. candidate in Cancer Biology; DOD Breast Cancer Predoctoral Trainee)
- Research Associate
- Mansoureh Sameni (Research Associate)
- Research Assistants
- Aruselvi Anbalagan
Some Lab Alumni
- Mamoun Ahram, Ph.D. (Ph.D. in Cancer Biology 1999), Assistant Dean for Testing Affairs and College Development, Faculty of Medicine, Mutah University, Mutah, Jordan.
- Isabelle Berquin, Ph.D. (Ph.D. in Cancer Biology 1995), Assistant Professor of Pathology, Wake Forest University, Winston-Salem, NC
- Dora Cavallo-Medved, Ph.D. (Postdoc 2000-04), Assistant Professor of Biological Sciences, University of Windsor, Ontario, Canada
- Michael Emmert-Buck, M.D.-Ph.D. (Ph.D. in Pharmacology 1989), Head, Pathogenetics Unit, Laboratory of Pathology, Advanced Technology Center, National Cancer Institute/NIH, Gaithersburg, MD
- Jennifer Koblinski, Ph.D. (Ph.D. in Cancer Biology 1999), Research Assistant Professor of Pathology, Northwestern University, Chicago, IL
- Tamara Turnsek Lah, Ph.D. (Postdoc 1985-87), Director, National Institute of Biology, Ljubljana, Slovenia
- Mona Mostafa Mohamed, Ph.D. (Avon/American Association for Cancer Research International Fellow 2005-07), Associate Professor of Biological Sciences, Cairo University, Cairo, Egypt - more...
- Greg Auner, Ph.D., Smart Sensors and Integrated Microsystems Program and Neb Duric, Ph.D., Karmanos Cancer Institute, Wayne State University, Detroit, MI
- Robert Gillies, Ph.D., Moffitt Cancer Center, Tampa, FL
- Simon Haywood, Ph.D. and Lynn Matrisian, Ph.D., Vanderbilt University, Nashville, TN
- Brian Hoffman, Ph.D. and Thomas Meade, Ph.D., Northwestern University, Evanston, IL
- Raymond Mattingly, Ph.D., Department of Pharmacology, Wayne State University, Detroit, MI
- Mona Mostafa Mohamed, Ph.D., Cairo University, Cairo, Egypt [more]
- Christoph Peters, M.D. and Thomas Reinheckel, M.D., Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-Universitat Freiburg, Germany
- John Reiners, Ph.D., Environmental Health Sciences Center for Cellular and Molecular Toxicology with Human Application, Wayne State University, Detroit, MI
- Boris Turk, Ph.D., Jozef Stefan Institute, Ljubljana, Slovenia
Selected Recent Publications
- Acuff, H.B., Sinnamon, M., Fingleton, B., Boone, B., Levy, S.E., Chen, X., Pozzi, A., Carbone, D.P., Schwartz, D.R., Moin, K., Sloane, B.F. and Matrisian, M.M.: Analysis of host- and tumor-derived proteinases using a custom dual species microarray reveals a protective role for stromal matrix metalloproteinase 12 in non-small cell lung cancer. Cancer Res. 66: 7968-7975, 2006. PMID: 16912171
- Schwartz, D.R., Moin, K., Yao, B., Matrisian, L.M., Coussens, L.M., Bugge, T.H., Fingleton, B., Acuff, H.B., Sinnamon, M., Nassar, H., Platts, A., Krawetz, S.A., Linebaugh, B.E. and Sloane, B.F.: Hu/Mu ProtIn oligonucleotide microarray: dual species array for profiling protease, protease inhibitor gene expression in tumors and their microenvironment. Mol Cancer Res 5: 443-454, 2007. PMID: 17510311
- Li, Q., Mullins, S.R., Sloane, B.F. and Mattingly, R.R.: p21-activated kinase 1 coordinates aberrant cell survival and pericellular proteolysis in a three-dimensional culture model for premalignant progression of human breast cancer. Neoplasia 10: 314-328, 2008. PMID: 18392133
- Jedeszko, C., Sameni, M., Olive, M.B., Moin, K. and Sloane, B.F.: Visualizing protease activity in living cells: from 2D to 4D. Current Protocols Cell Biol. 39: 4.20.1-4.20.15, 2008. Cancer Res. 69: 9148-9155, 2009. PMID: 19920187
- Trivedi, E.R., Harney, A.S., Olive, M.B., Podgorski, I., Moin, K., Sloane, B.F., Barrett, A.G.M., Meade, T.J. and Hoffman, B.M.: Chiral porphyrazine near-IR optical imaging agent exhibiting preferential tumor accumulation. Proc. Natl. Acad. Sci. USA 26: 1284-8, 2010; published online 12/23/09. PMID: 20080563
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Avon Foundation International Scholars in Training
The cancer degradome